Cellular and circuit mechanisms of the therapeutic action of inhaled nitrous oxide in rodent models of chronic stress

吸入一氧化二氮对慢性应激啮齿动物模型治疗作用的细胞和回路机制

• 批准号: 10712012
• 负责人: JOSEPH CICHON
• 金额: $ 40.63万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10712012
• 关键词: Acute; Aftercare; Anesthetics; Animal Model; Animals; Antidepressive Agents; Automobile Driving; Behavioral; Brain region; Calcium; Chronic stress; Clinical Research; Dissociative Anesthetics; Dose; Electrophysiology (science); Foundations; Goals; Hour; Image; Imaging Techniques; Individual; Inhalation; Intervention; Intravenous; Involutional Depression; Ketamine; Link; Mediating; Mental Depression; Mission; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; National Institute of General Medical Sciences; Neocortex; Neuronal Plasticity; Neurons; Nitrous Oxide; Patients; Refractory; Resistance; Rodent Model; Structure; Synapses; Techniques; Testing; Therapeutic; Therapeutic Effect; Time; Work; antagonist; clinical effect; clinical practice; depressive symptoms; disability; hippocampal pyramidal neuron; improved; in vivo imaging; innovation; neocortical; neuropsychiatric disorder; novel; pharmacologic; stem

Project Summary/Abstract Depression is the leading cause of disability worldwide and new treatments are needed. This therapeutic challenge stems from the fact that depression involves deficits distributed among neuronal subtypes and multiple brain regions. A growing body of clinical research demonstrates that a single dose of N-methyl-D-aspartate receptor , induce rapid and durable improvements in depressive symptoms persisting for days to weeks in patients refractory to conventional antidepressant therapies. Despite nitrous oxide being the oldest and one of the safest anesthetics in current (NMDA-R) antagonists, inhaled nitrous oxide or intravenous ketamine clinical practice, our understanding of how nitrous oxide modulates neuronal activity and circuit function to produce its clinical effects is extraordinarily limited. While it has been hypothesized that the therapeutic effect of NMDA-R antagonists is related to their ability to induce plasticity, the mechanisms that initiate and sustain this plasticity remain unclear. By combining in vivo imaging of synaptic structure, functional calcium imaging, electrophysiology, and behavioral recordings, this proposal will test an innovative hypothesis that changes in neuronal activity imposed by nitrous oxide acutely, automatically give rise to sustained plasticity through activity-dependent mechanisms. This hypothesis is based on extensive work on activity- dependent plasticity in the neocortex and on our own novel preliminary results showing that nitrous oxide specifically and directly activates layer 5 pyramidal neurons, which mediate cortico-cortical and cortico- subcortical connectivity, through a novel mechanism. All animal models and techniques have been established in the studies that generated the preliminary results, making the proposal highly achievable. In line with the mission of the NIGMS, the immediate goal of this proposal is to lay the foundation for advances in the treatment of depression by understanding the mechanisms of action of nitrous oxide in cortical circuits. Such an understanding may explain how acute pharmacologic interventions can lead to sustained therapeutic benefits in the setting of depression and potentially other neuropsychiatric diseases.

项目摘要/摘要 抑郁症是全球残疾的主要原因，需要新的治疗方法。这种治疗性 挑战源于以下事实：抑郁涉及分布在神经元亚型之间的缺陷和多种 大脑区域。越来越多的临床研究表明，单剂量的N-甲基-D-天冬氨酸 受体，诱导快速耐用 抑郁症状的改善持续数天到几周的患者对常规的耐火性 抗抑郁药。尽管一氧化二氮是最古老，也是当前最安全的麻醉剂之一 （NMDA-R）拮抗剂，吸入的一氧化二氮或静脉注射氯胺酮 临床实践，我们对一氧化二氮如何调节神经元活动和电路功能的理解 产生其临床效应受到极大的限制。虽然假设 NMDA-R拮抗剂与诱导可塑性的能力有关，启动和维持的机制 可塑性仍然不清楚。通过结合突触结构的体内成像，功能性钙成像， 电生理学和行为记录，该提案将检验一个创新的假设， 一氧化二氮敏锐地施加的神经元活性的变化，会自动产生持续 通过活动依赖机制的可塑性。该假设基于有关活动的广泛工作 - 新皮层的依赖性可塑性和我们自己的新型初步结果表明一氧化二氮 具体并直接激活5层锥体神经元，该神经元介导皮质皮质和皮质 - 皮层连通性，通过一种新型机制。所有动物模型和技术均已建立 在产生初步结果的研究中，该提案高度可以实现。与 纽约的使命，该提案的直接目标是为进步奠定基础 通过了解皮质回路中一氧化二氮的作用机制来治疗抑郁症。 这样的理解可以解释急性药理干预措施如何导致持续治疗 在抑郁症和可能其他神经精神疾病的情况下的好处。